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- New York: Columbia University Medical Center
- Ontario: Samuel Lunenfeld Research Institute of Mt. Sinai Hospital
- Philadelphia: Fox Chase Cancer Center, the University of Pennsylvania and The Children's Hospital of Philadelphia
- San Francisco Bay Area: Cancer Prevention Institute of California
- Utah: Huntsman Cancer Institute
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Non-invasive optical spectroscopic monitoring of breast development during puberty
Authors: Lilge L, Terry MB, Walter J, Pinnaduwage D, Glendon G, Hanna D, Tammemagi ML, Bradbury A, Buys S, Daly M, John EM, Knight JA, Andrulis IL.
Citation: Breast Cancer Res. 2017 Feb 6;19(1):12. doi: 10.1186/s13058-017-0805-x.
Pubmed Link: https://www.ncbi.nlm.nih.gov/pubmed/28166807
BACKGROUND: Tanner staging (TS), a five-stage classification indicating no breast tissue (TS1) to full breast development (TS5), is used both in health research and clinical care to assess the onset of breast development (TS2) and duration in each stage. Currently, TS is measured both visually and through palpation but non-invasive methods will improve comparisons across settings.
METHODS: We used optical spectroscopy (OS) measures from 102 girls at the Ontario site of the LEGACY girls study (average age 12 years, range 10.0-15.4 years) to determine whether breast tissue optical properties map to each TS. We further examined whether these properties differed by age, body mass index (BMI), and breast cancer risk score (BCRS) by examining the major principal components (PC).
RESULTS: Age and BMI increased linearly with increasing TS. Eight PCs explained 99.9% of the variation in OS data. Unlike the linear increase with age and BMI, OS components had distinct patterns by TS: the onset of breast development (TS1 to TS2) was marked by elevation of PC3 scores indicating an increase in adipose tissue and decrease in signal from the pectoral muscle; transition to TS3 was marked by elevation of PC6 and PC7 and decline of PC2 scores indicating an increase in glandular or dense tissue; and transition to TS4+ by decline of PC2 scores representing a further increase in glandular tissue relative to adipose tissue. Of the eight PCs, three component scores (PC4, PC5, and PC8) remained in the best-fitting model of BCRS, suggesting different levels of collagen in the breast tissue by BCRS.
CONCLUSIONS: Our results suggest that serial measures of OS, a non-invasive assessment of breast tissue characteristics, can be used as an objective outcome that does not rely on visual inspection or palpation, for studying drivers of breast development.
Comparison of Clinical, Maternal, and Self Pubertal Assessments: Implications for Health Studies.
Authors: Terry MB, Goldberg M, Schechter S, Houghton LC, White ML, O'Toole K, Chung WK, Daly MB, Keegan TH, Andrulis IL, Bradbury AR, Schwartz L, Knight JA, John EM, Buys SS.
Citation: Pediatrics 2016 Jul; 138 (1). doi: 10.1542/peds.2015-4571. Epub 2016 June 8.
Pubmed Link: http://www.ncbi.nlm.nih.gov/pubmed/27279647
BACKGROUND: Most epidemiologic studies of puberty have only 1 source of pubertal development information (maternal, self or clinical). Interpretation of results across studies requires data on reliability and validity across sources.
METHODS: The LEGACY Girls Study, a 5-site prospective study of girls aged 6 to 13 years (n = 1040) collected information on breast and pubic hair development from mothers (for all daughters) and daughters (if ≥10 years) according to Tanner stage (T1-5) drawings. At 2 LEGACY sites, girls (n = 282) were also examined in the clinic by trained professionals. We assessed agreement (κ) and validity (sensitivity and specificity) with the clinical assessment (gold standard) for both the mothers' and daughters' assessment in the subcohort of 282. In the entire cohort, we examined the agreement between mothers and daughters.
RESULTS: Compared with clinical assessment, sensitivity of maternal assessment for breast development was 77.2 and specificity was 94.3. In girls aged ≥11 years, self-assessment had higher sensitivity and specificity than maternal report. Specificity for both mothers and self, but not sensitivity, was significantly lower for overweight girls. In the overall cohort, maternal and daughter agreement for breast development and pubic hair development (T2+ vs T1) were similar (0.66, [95% confidence interval 0.58-0.75] and 0.69 [95% confidence interval 0.61-0.77], respectively), but declined with age. Mothers were more likely to report a lower Tanner stage for both breast and pubic hair compared with self-assessments.
CONCLUSIONS: These differences in validity should be considered in studies measuring pubertal changes longitudinally when they do not have access to clinical assessments.
The LEGACY Girls Study: Growth and development in the context of breast cancer family history.
Authors: John EM, Terry MB, Keegan TH, Bradbury AR, Knight JA, Chung WK, Frost CJ, Lilge L, Patrick-Miller L, Schwartz LA, Whittemore AS, Buys SS, Daly MB, Andrulis IL.
Citation: Epidemiology 2016 Jan 29 [Epub ahead of print].
Pubmed Link: http://www.ncbi.nlm.nih.gov/pubmed/26829160
BACKGROUND: Although the timing of pubertal milestones has been associated with breast cancer risk, few studies of girls' development include girls at increased breast cancer risk due to their family history.
METHODS: The LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth) Girls Study was initiated in 2011 in the USA and Canada to assess the relation between early-life exposures and intermediate markers of breast cancer risk (e.g., pubertal development, breast tissue characteristics) and to investigate psychosocial well-being and health behaviors in the context of family history. We describe the methods used to establish and follow a cohort of 1,040 ages 6-13 years at baseline, half with a breast cancer family history, and the collection of questionnaire data (family history, early-life exposures, growth and development, psychosocial and behavioral), anthropometry, biospecimens, and breast tissue characteristics using optical spectroscopy.
RESULTS: During this initial 5-year phase of the study, follow-up visits are conducted every six months for repeated data and biospecimen collection. Participation in baseline components was high (98% for urine, 97.5% for blood or saliva, and 98% for anthropometry). At enrollment, 77% of girls were pre-menarcheal and 49% were at breast Tanner stage T1.
CONCLUSIONS: This study design allows thorough examination of events affecting girls' growth and development and how they differ across the spectrum of breast cancer risk. A better understanding of early-life breast cancer risk factors will be essential to enhance prevention across the lifespan for those with and without a family history of the disease.
Human subjects protection: an event monitoring committee for research studies of girls from breast cancer families.
Authors: Harris D, Patrick-Miller L, Schwartz L, Lantos J, Daugherty C, Daly M, Andrulis IL, Buys SS, Chung WK, Frost CJ, John EM, Keegan TH, Knight KA, Terry MB, Bradbury AR.
Citation: J Adolesc Health. 2014 Sep;55(3):352-7. doi: 10.1016/j.jadohealth.2014.03.007. Epub 2014 May 17.
Pubmed Link: http://www.ncbi.nlm.nih.gov/pubmed/24845866
PURPOSE: Researchers must monitor the safety of research participants, particularly in studies involving children and adolescents. Yet, there is limited guidance for the development and implementation of oversight committees for psychosocial, behavioral intervention, and observational studies.
METHODS: We implemented a model for an Event Monitoring Committee (EMC) in three related studies recruiting 6- to 19-year-old girls from families with and without breast cancer.
RESULTS: The EMC model can be valuable for investigators and local institutional review boards when additional oversight is desired. Recommendations are provided and intended to be broadly applicable to a wide range of research activities designed to improve the health of children, adolescents, and families. EMC goals, membership, and procedures for monitoring and assessing risks and benefits should be defined but should also be flexible and tailored to the study design and population. The EMC model also provides an independent comprehensive, study-wide oversight mechanism for multicenter psychosocial, behavioral intervention, and observational studies.
CONCLUSIONS: An EMC provides an alternative oversight approach where additional independent assessment and oversight of study-related risks are desired, particularly in the setting of vulnerable populations, children and adolescents, or where risks nontraditional to the medical field (i.e., social, emotional, or cultural) are possible.
Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study.
Authors: Wu HC, Wang Q, Chung WK, Andrulis IL, Daly MB, John EM, Keegan TH, Knight J, Bradbury AR, Kappil MA, Gurvich I, Santella RM, Terry MB.
Citation: Epigenetics. 2014 July;9(7):929-33. doi: 10.4161/epi.28902. Epub 2014 Apr 22.
Pubmed Link: http://www.ncbi.nlm.nih.gov/pubmed/24756002
Abstract: Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE-1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources.
Global DNA methylation levels in girls with and without a family history of breast cancer.
Authors: Wu HC, John EM, Ferris JS, Keegan TH, Chung WK, Andrulis I, Delgado-Cruzata L, Kappil M, Gonzalez K, Santella RM, Terry MB.
Citation: Epigenetics. 2011 Jan;6(1):29-33. doi: 10.4161/epi.6.1.13393. Epub 2011 Jan 1.
Pubmed Link: http://www.ncbi.nlm.nih.gov/pubmed/20930546
Abstract: Lower levels of global DNA methylation in white blood cell (WBC) DNA have been associated with adult cancers. It is unknown whether individuals with a family history of cancer also have lower levels of global DNA methylation early in life. We examined global DNA methylation in WBC (measured in three repetitive elements, LINE1, Sat2 and Alu, by MethyLight and in LINE1 by pyrosequencing) in 51 girls ages 6-17. Compared to girls without a family history of breast cancer, methylation levels were lower for all assays in girls with a family history of breast cancer, and statistically significantly lower for Alu and LINE1 pyrosequencing. After adjusting for age, body mass index (BMI), and Tanner stage, only methylation in Alu was associated with family history of breast cancer. If these findings are replicated in larger studies, they suggest that lower levels of global WBC DNA methylation observed later in life in adults with cancer may also be present early in life in children with a family history of cancer.
A qualitative study evaluating parental attitudes towards the creation of a female youth cohort (LEGACY) in the Breast Cancer Family Registry.
Authors: Glendon G, Frost CJ, Andrulis IL, Hanna D, John EM, Phipps AI, Thompson A, Venne V, Ritvo P.
Citation: Psychooncology. 2010 Jan;19(1):93-101. doi: 10.1002/pon.1543.
Pubmed Link: http://www.ncbi.nlm.nih.gov/pubmed/19415783
OBJECTIVES: Expanding the existing Breast Cancer Family Registry (BCFR) to enroll daughters aged 6-17 years in a prospective cohort study named LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth) offers the opportunity to study the effects of genetic and environmental exposures in youth on adult breast cancer risk. Few studies have assessed parents' willingness to enroll their daughters in genetic epidemiological cohort studies. Since BCFR parents are the gatekeepers of their daughters' future enrollment, it is important to explore their interests and attitudes towards LEGACY.
METHODS: Semi-structured telephone interviews were conducted with 85 BCFR participant parents at 3 BCFR sites in Ontario, Canada, and in Utah and Northern California. We explored parents' thoughts and feelings (interests and attitudes) regarding their daughters' enrollment in LEGACY and different data collection modalities. Qualitative analysis of audiotaped interviews was carried out utilizing an inductive content analysis.
RESULTS: Parents' acceptance of three data collection modalities were 92% (78/85) for questionnaire data, 87% (74/85) for biological samples and 63% (46/73) for physical examination for pubertal staging. The parents' primary motivation for participation was altruistic. Their concerns regarding their daughters' participation centered on exacerbating awkward pubertal feelings, increasing cancer anxiety, respecting autonomy and maturity, privacy and future use of data and logistical impediments.
CONCLUSION: Parents demonstrated a high level of interest in the creation of LEGACY. Their motivation to participate was balanced by their desire to protect their daughters from undue harm. These interviews contributed valuable information for the design of LEGACY.
Related Publications by LEGACY Investigators.
Terry MB, Bradbury AR. Family-based Breast Cancer Prevention Efforts in Adolescence. Pediatrics. 2016 Nov; 138 (Supplement 1): S78-S80. doi: 10.1542/peds.2015-4268K.
Terry MB, Forman MR. Empowering Pediatricians to Prevent Chronic Disease Across Generations. Pediatrics. 2016 Nov; 138 (Supplement 1): S92-S94. doi: 10.1542/peds.2015-4268M.
Schooling CM, Houghton LC, Terry MB. Potential Intervention Targets in Utero and Early Life for Prevention of Hormone Related Cancers. Pediatrics. 2016 Nov; 138 (Supplement 1): S22-S33. doi: 10.1542/peds.2015-4268E.
Michels KB, Cohn BA, Goldberg M, Flom JD, Dougan M, Terry MB. Maternal Anthropometry and Mammographic Density in Adult Daughters. Pediatrics. 2016 Nov; 138 (Supplement 1): S34-S41. doi: 10.1542/peds.2015-4268F.
Blackmore KM, Knight JA, Walter J, Lilge L. The Association between Breast Tissue Optical Content and Mammographic Density in Pre- and Post-Menopausal Women. PLoS One. 2015 Jan 15;10(1):e0115851. doi: 10.1371/journal.pone.0115851. eCollection 2015. PMID: 25590139
Houghton LC, Cooper GD, Bentley GR, Booth M, Chowdhury OA, Troisi R, Ziegler RG, Hoover RN, Katki HA. A migrant study of pubertal timing and tempo in British-Bangladeshi girls at varying risk for breast cancer. Breast Cancer Res. 2014 Nov 15;16(6):469. [Epub ahead of print] PMID: 25398700
Houghton LC, Cooper GD, Booth M, Chowdhury OA, Troisi R, Ziegler RG, Katki HA, Hoover RN, Bentley GR.Childhood environment influences adrenarcheal timing among first-generation Bangladeshi migrant girls to the UK. PLoS One. 2014 Oct 13;9(10):e109200. doi: 10.1371/journal.pone.0109200. eCollection 2014. PMID: 25309977
Hanna D, Glendon G, Knight J, Lilge L, BordeleauL, Armel S, Terespolsky D, Panchal S, Carroll J, Andrulis I. LEGACY Girls Study (Lessons in Epidemiology and Genetics of Adult Cancer from Youth): Recruitment and Retention Within the Ontario Site [abstract]. In: Current Oncology; 2014 Vol 21 (2):e381. Abstract nr P073.
DeRouen MC, Gomez SL, Press DJ, Tao L, Kurian AW, Keegan THM. A population-based observational study of treatment and survival for adolescent and young adult females with breast cancer. J Adolesc Young Adult Oncol 2013 Sep; 2(3):95-103. PMID: 24066271
La Merrill M, Cirillo PM, Terry MB, Krigbaum NY, Flom JD, Cohn BA. Prenatal Exposure to the Pesticide DDT and Hypertension Diagnosed in Women before Age 50: A Longitudinal Birth Cohort Study. Environ Health Perspect. 2013 May;121(5):594-9. doi: 10.1289/ehp.1205921. Epub 2013 Mar 7. PMID: 23591545
Keegan THM, Press DJ, Tao L, DeRouen MC, Kurian AW, Clarke CA, Gomez SL. Impact of breast cancer subtypes on three-year survival among adolescent and young adult women. Breast Cancer Res 2013; 15(5):R95. PMID: 24131591
Cohn BA, Terry MB, Plumb M, Cirillo PM. Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50. Breast Cancer Res Treat. 2012 Nov;136(1):267-75. doi: 10.1007/s10549-012-2257-4. Epub 2012 Sep 28. PMID: 23053646
Keegan THM, DeRouen MC, Press DJ, Kurian AW, Clarke CA. Occurrence of breast cancer subtypes in adolescent and young adult women. Breast Cancer Res 2012 Mar;14(2):R55. PMID: 22452927
Hanna D, Glendon G, Knight J, Lilge L, Bordeleau L, Terespolsky D, Andrulis I. LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth): What Parents and Daughters Taught Us in the Ontario LEGACY Pilot Study [abstract]. In: Current Oncology; 2012 Vol 19 (2):e101. Abstract nr P052.
Lumey LH, Terry MB, Delgado-Cruzata L, Wang Q, Susser E, McKeague I, Santella RM. Adult global DNA methylation in relation to pre-natal nutrition. International Journal of Epidemiology 2012 Feb;41(1):116-23. doi: 10.1093/ije/dyr137. Epub 2011 Sep 29.2011. PMID: 22422450
Terry MB, Schaefer CA, Flom JD, Wei Y, Tehranifar P, Liao Y, Buka S, Michels KB. Prenatal smoke exposure and mammographic density in mid-life. Journal of Developmental Origins of Health and Disease 2011, 2(6), 340–352. doi: 10.1017/S2040174411000614. PMID: 23378890
Susser E, S. Buka S, Schaefer CA, Andrews H, Cirillo PM, Factor-Litvak P, Gillman M, Goldstein JM, Ivey Henry P, Lumey LH, McKeague IW, Michels KB, Terry MB, Cohn B for the EDAH Team. The Early Determinants of Adult Health Study. Journal of Developmental Origins of Health and Disease 2011, 2(6), 311–321. PMID: 25126404
Flom JD, Ferris JS, Liao Y, Tehranifar P, Belessiotis Richards C, Cho YH, Gonzalez K, Santella RM, Terry MB. Prenatal Smoke Exposure and Genomic DNA Methylation in a Multi-ethnic Urban Birth Cohort. Cancer Epidemiol Biomarkers Prev. 2011 Dec; 20(12):2518-23. doi: 10.1158/1055-9965.EPI-11-0553. Epub 2011 Oct 12. PMID: 21994404
Sangaramoorthy M, Phipps, AI, Horn-Ross PL, Koo J, John EM. Early-life factors and breast cancer risk in Hispanic women: The role of adolescent body size. Cancer Epi Biomarker Prev 2011 Dec; 20(12): 2572-82. doi: 10.1158/1055-9965.EPI-11-0848. Epub 2011 Nov 4. PMID: 22056503
James-Todd T, Terry MB, Rich-Edwards J, Deierlein A, Senie R. Childhood hair product use and earlier age at menarche in a racially diverse study population: a pilot study. Ann Epidemiol. 2011 Jun;21(6):461-5. Epub 2011 Mar 21. PMID: 21421329
Terry MB, Wei Y, Esserman D, McKeague I, Susser E. Pre- and Postnatal Determinants of Childhood Body Size: cohort and sibling analyses. Journal of the Developmental Origins of Health and Disease 2011 Apr; 2(2), 99–111. doi: 10.1017/S2040174411000067. PMID: 25140924
James-Todd T, Tehranifar P, Rich-Edwards J, Titievsky L, Terry MB. The impact of socioeconomic status across early life on age at menarche among a racially diverse population of girls. Ann Epidemiol. 2010 Nov;20(11):836-42. doi: 10.1016/j.annepidem.2010.08.006. PMID: 20933190
Ferris JS, Flom JD, Tehranifar P, Mayne ST, Terry MB. Prenatal and childhood environmental tobacco smoke exposure and age at menarche. Paediatr Perinat Epidemiol. 2010 Nov;24(6):515-23. doi: 10.1111/j.1365-3016.2010.01154.x. Epub 2010 Aug 24. PMID: 2095522
Knight JA, Blackmore KM, Wong J, Tharmalingam S, Lilge L. Optical spectroscopy of the breast in premenopausal women reveals tissue variation with age and parity. Medical Physics 2010 Feb; 37(2):419-26. PMID: 20229850
Hanna D, Glendon G, Maloney E, Knight ., Lilge L, Koller D, and Andrulis IL. The Establishment of a Cohort of Girls in Ontario Breast Cancer Families [Abstract]. In: Current Oncology; 2009 Vol 16 (5): 92. Abstract nr P006
Tehranifar P, Liao Y, Flom J, Terry MB. Validity of Self-reported Birthweight by Adult Women: Sociodemographic Influences and Implications for Lifecourse Studies. American Journal of Epidemiology 2009 Oct 1; 170(7): 910-7. doi: 10.1093/aje/kwp205. Epub 2009 Sep 11. PMID: 19748903
Wei Y, Flom J, Tehranifar P. Birthweight, Postnatal Growth, and Age at Menarche. American Journal of Epidemiology 2009 July 1; 170(1): 72-9. doi: 10.1093/aje/kwp095. Epub 2009 May 13. PMID: 19439580
Terry, MB, Tehranifar P, Flom J, Susser E. Studying the Role of Early Life on Women’s Health: The New York Women’s Birth Cohort. Pediatric and Perinatal Epidemiology 2009 Sept; 23(5): 431-45. doi: 10.1111/j.1365-3016.2009.01061.x. PMID: 19689494
Tehranifar P, Liao Y, Ferris J, Terry MB. Life course Socioeconomic Conditions, Passive Tobacco Exposure and Adult Women’s Cigarette Smoking Status. Cancer Causes and Control 2009 Aug; 20(6): 867-76. doi: 10.1007/s10552-009-9307-1. Epub 2009 Feb 24. PMID: 19238563
Blackmore KM, Dick S, Lockwood G, Knight J, Lilge L. Estimation of mammographic density (MD) on an interval scale by transillumination breast spectroscopy (TIBS). J Biomed Opt 2008 Nov-Dec; 13(6):064030. doi: 10.1117/1.3041498. PMID: 19123676
Terry MB, Ferris J, Pilsner R, Flom J, Santella RM, Gamble MV, Susser E. Genomic DNA methylation among women in a multiethnic New York City birth cohort. Cancer Epidemiol Biomarkers Prev 2008 Sep;17(9):2306-10. doi: 10.1158/1055-9965.EPI-08-0312. PMID: 18768498
Blackmore K, Knight JA, Lilge L. The association between transillumination breast spectroscopy (TiBS) parameters and quantitative mammographic features of the breast. Cancer Epidemiol Biomarkers Prev 2008 May; 17(5):1043-50. doi: 10.1158/1055-9965.EPI-07-2658. PMID: 18483324
Blackmore K, Knight JA, Jong R, Lilge L. Assessing breast tissue density by transillumination breast spectroscopy (TIBS): an intermediate indicator of cancer risk. Br J Radiol 2007 Jul; 80(955):545-56. Epub 2007 May 30. PMID:17537757
Terry MB, Wei Y, Esserman D. Maternal, Birth, and Early-Life Influences on Adult Body Size in Women. Am J Epidemiol. 2007 Jul 1; 166(1): 5-13. Epub 2007 Apr 29. PMID: 17470452
John EM, Koo J, Schwartz GG. Sun exposure and prostate cancer risk: Evidence for a protective effect of early life exposure. Cancer Epidemiol Biomarkers Prev 2007 Jun;16:1283-1286. PMID: 17548698
Susser E, Terry MB. A conception-to-death cohort. Lancet 2003 Mar 8; 361 (9360): 797-8. PMID: 12642043